Synthesis and evaluation of in vitro antiviral activity of 2-[3-(substituted phenyl)-4,5-dihydro-1H-5-pyrazolyl]benzofuran-3-yl chloride derivatives

Figures & data

Table 1.  Physical constants of the compound.

Code	R	Molecular Formula	Molecular Weight	% yield	Melting Point °C
2a	Phenyl	C17H11ClO2	282	78	140–42
2b	4-chloro phenyl	C17H10Cl2O2	317	87	148–150
2c	4-methyl phenyl	C18H13ClO2	296	76	126–28
2d	4-nitro phenyl	C17H10ClNO4	327	70	182–84
2e	4-amino phenyl	C17H12ClNO2	297	84	184–86
2f	4-hydroxy phenyl	C17H11ClO3	298	76	210–12
2g	2-hydroxy phenyl	C17H11ClO3	298	76	110–12
2h	4-methoxy phenyl	C18H13ClO3	312	98	106–08
2i	2,4-dihydroxy phenyl	C17H11ClO4	314	80	98–100
2j	2,4-dimethoxy phenyl	C19H15ClO4	342	84	138–40
2k	3,4-dimethoxy phenyl	C19H15ClO4	342	89	172–74
2l	4-hydroxy-3-methyl phenyl	C18H13ClO3	312	76	202–04
2m	4-hydroxy-2-metyl phenyl	C18H13ClO3	312	76	160–62
3a	Phenyl	C17H13ClN2O	296	78	126–28
3b	4-chloro phenyl	C17H12Cl2N2O	331	82	66–68
3c	4-methyl phenyl	C18H15ClN2O	310	80	144–46
3d	4-nitro phenyl	C17H12ClN3O3	341	74	108–10
3e	4-amino phenyl	C17H14ClN3O	311	70	120–22
3f	4-hydroxy phenyl	C17H13ClN2O2	312	78	26870
3g	2-hydroxy phenyl	C17H13ClN2O2	312	82	148–50
3h	4-methoxy phenyl	C18H15ClN2O2	326	87	82–84
3i	2,4-dihydroxy phenyl	C17H13ClN2O3	328	74	140–42
3j	2,4-dimethoxy phenyl	C19H17ClN2O3	356	78	132–34
3k	3,4-dimethoxy phenyl	C19H17ClN2O3	356	78	98–100
3l	4-hydroxy-3-methyl phenyl	C18H15ClN2O2	326	76	232–38
3m	4-hydroxy-2-metyl phenyl	C18H15ClN2O2	326	76	150–54

Scheme 1.  Synthesis of tilted compounds.

Table 2.  Cytotoxicity and antiviral activity of compounds in Crandell-Rees Feline Kidney (CRFK) cell cultures.

Compound	CC50^a (μg/ml)	EC50^b (μg/ml)
		Feline Corona Virus (FIPV)	Feline Herpes Virus
2a	6.1	>4	>4
2b	16.2	>4	>4
2c	27.7	>20	>20
2d	52.9	>20	>20
2e	65.9	>20	>20
2f	8.0	>4	>4
2g	30.0	>20	>20
2h	52.1	>20	>20
2i	3.4	>0.8	>0.8
2j	32.6	>20	>20
2k	>100	>100	>100
2l	11.4	>4	>4
2m	0.16	>0.32	>0.32
3a	9.9	>4	>4
3b	12.6	3.8	>4
3c	11.5	>4	>4
3d	11.8	>4	>4
3e	34.0	>20	>20
3f	>100	>100	81.5
3g	81.6	>20	>20
3h	16.0	>4	>4
3i	15.3	>4	>4
3j	26.2	>20	>20
3k	>100	>100	>100
3l	>100	>100	>100
3m	4.9	>4	>4
Ganciclovir (μM)	>100	>100	4.0

^a50% Cytotoxic concentration, as determined by measuring the cell viability with the colorimetric formazan-based MTS assay.

^b50% Effective concentration, or concentration producing 50% inhibition of virus-induced cytopathic effect, as determined by measuring the cell viability with the colorimetric formazan-based MTS assay.

Table 3.  Cytotoxicity and antiviral activity of compounds in human embryonic lung (HEL) cell cultures.

Compound	Minimum cytotoxic concentration^a (μg/ml)	EC50^b (μg/ml)
		Herpes simplex virus-1 (KOS)	Herpes simplex virus-2 (G)	Vaccinia virus	Vesicular stomatitis virus	Herpes simplex virus-1 TK- KOS ACV^r
2a	>100	>100	>100	>100	>100	>100
2b	>100	>100	>100	>100	>100	>100
2c	≥20	>20	>20	>20	>20	>20
2d	>100	>100	>100	>100	>100	>100
2e	20	>4	>4	>4	>4	>4
2f	4	>0.8	>0.8	>0.8	>0.8	>0.8
2g	≥4	>4	>4	>4	>4	>4
2h	20	>4	>4	>4	>4	>4
2i	≥0.8	>0.8	>0.8	>0.8	>0.8	>0.8
2j	>100	>100	>100	>100	>100	>100
2k	>100	>100	>100	>100	>100	>100
2l	20	>4	>4	>4	>4	>4
2m	20	>4	>4	>4	>4	>4
3a	20	>4	>4	>4	>4	>4
3b	20	>4	>4	>4	>4	>4
3c	20	>4	>4	>4	>4	>4
3d	≥20	>20	>20	>20	>20	>20
3e	100	>20	>20	>20	>20	>20
3f	20	>4	>4	>4	>4	>4
3g	≥20	>20	>20	>20	>20	>20
3h	≥20	>20	>20	>20	>20	>20
3i	20	>4	>4	>4	>4	>4
3j	20	>4	>4	>4	>4	>4
3k	20	>4	>4	>4	>4	>4
3l	20	>4	>4	>4	>4	>4
3m	20	>4	>4	>4	>4	>4
Brivudin (μM)	>250	0.08	250	50	>250	>250
Ribavirin (μM)	>250	50	>250	>250	>250	>250
Cidofovir (μM)	>250	2	2	10	>250	2
Ganciclovir (μM)	>100	0.16	0.16	>100	>100	20

^aRequired to cause a microscopically detectable alteration of normal cell morphology.

^bRequired to reduce virus-induced cytopathogenicity by 50 %.

Table 4.  Cytotoxicity and antiviral activity of compounds in HeLa cell cultures.

Compound	Minimum cytotoxic concentration^a (μg/ml)	EC50^b (μg/ml)
		Vesicular stomatitis virus	Coxsackie virus B4	Respiratory syncytial virus
2a	100	>20	>20	>20
2b	>100	>100	>100	>100
2c	100	>20	>20	>20
2d	≥20	>20	>20	>20
2e	≥20	>20	>20	>20
2f	4	>0.8	>0.8	>0.8
2g	≥20	>20	>20	>20
2h	100	>20	>20	>20
2i	0.8	>0.16	>0.16	>0.16
2j	100	>20	>20	>20
2k	100	>20	>20	>20
2l	20	>4	>4	>4
2m	20	>4	>4	>4
3a	20	4	>4	>4
3b	4	>0.8	>0.8	>0.8
3c	≥4	>4	>4	>4
3d	4	>0.8	>0.8	>0.8
3e	20	>4	>4	>4
3f	20	>4	>4	4
3g	4	>0.8	>0.8	>0.8
3h	4	>0.8	>0.8	>0.8
3i	20	>4	>4	>4
3j	100	>20	>20	>20
3k	20	>4	>4	>4
3l	≥20	>20	>20	>20
3m	≥4	>4	>4	>4
DS-5000	>100	4	>100	1
(S)-DHPA (μM)	>250	>250	>250	>250
Ribavirin (μM)	>250	22	146	10

^aRequired to cause a microscopically detectable alteration of normal cell morphology.

^bRequired to reduce virus-induced cytopathogenicity by 50 %.

Table 5.  Cytotoxicity and antiviral activity of compounds in Vero cell cultures.

Compound	Minimum cytotoxic concentration^a (μg/ml)	EC50^b (μg/ml)
		Para-influenza-3 virus	Reovirus-1	Sindbis virus	Coxsackie virus B4	Punta Toro virus
2a	20	>4	>4	>4	>4	>4
2b	100	>20	>20	>20	>20	>20
2c	≥20	>20	>20	>20	>20	>20
2d	100	>20	>20	>20	>20	>20
2e	100	>20	>20	>20	>20	>20
2f	≥4	>4	>4	>4	>4	>4
2g	20	>4	>4	>4	>4	>4
2h	100	>20	>20	>20	>20	>20
2i	≥4	>4	>4	>4	>4	>4
2j	100	>20	>20	>20	>20	>20
2k	100	>20	>20	>20	>20	>20
2l	≥20	>20	>20	>20	>20	>20
2m	20	>4	>4	>4	>4	>4
3a	20	>4	>4	>4	>4	>4
3b	≥4	>4	>4	>4	>4	>4
3c	20	>4	>4	>4	>4	>4
3d	≥4	>4	>4	>4	>4	>4
3e	20	>4	>4	>4	>4	>4
3f	20	>4	>4	>4	>4	>4
3g	≥4	>4	>4	>4	>4	>4
3h	≥4	>4	>4	>4	>4	>4
3i	20	>4	>4	>4	>4	>4
3j	100	>20	>20	>20	>20	>20
3k	20	>4	>4	>4	>4	>4
3l	100	>20	>20	>20	>20	>20
3m	20	>4	>4	>4	>4	>4
DS-5000	>100	>100	>100	>100	>100	100
(S)-DHPA (μM)	>250	250	>250	>250	>250	>250
Ribavirin (μM)	>250	45	146	146	>250	146

^aRequired to cause a microscopically detectable alteration of normal cell morphology.

^bRequired to reduce virus-induced cytopathogenicity by 50 %.